Insulin resistance contributes to the pathogenesis of several human diseases such as obesity and non-insulin-dependent diabetes mellitus. We have investigated patients with genetic forms of extreme insulin resistance to gain insight into biochemical defects which give rise to disease. 1. Decreased receptor biosynthesis. In some patients, cells contain a decreased level of insulin receptor mRNA. This, in turn leads to decreases in the rate of receptor biosynthesis and the number of insulin receptors on the cell surface. It seems likely that the primary defect is a mutation in the rate at which the receptor gene is transcribed. We are characterizing the regulatory regions of the insulin receptor gene. 2. Impaired transport to the plasma membrane. In some insulin resistant patients whose cultured cells possess normal levels of receptor mRNA and appear to biosynthesize receptors at a normal rate. There appears to be an impediment to the insertion of the receptors in the plasma membrane. Analysis of the inheritance of restriction fragment length polymorphisms has suggested that the mutation causing insulin resistance is linked to the insulin receptor gene. 3. Defect in transmembrane signalling. With some insulin resistant patients, the cultured cells possess a normal number of insulin receptors, but the receptors are qualitatively abnormal. These defects have been identified either because of abnormalities in binding affinity or defects in the receptor- associated tyrosine kinase activity. We are presently attempting to obtain cDNA clones encoding patients' insulin receptors to identify mutations in the structural gene for the receptor.